Possible anti-oxidant and neuroprotective mechanisms of zolpidem in attenuating typical anti-psychotic-induced orofacial dyskinesia-A biochemical and neurochemical study

Tardive dyskinesia is a serious motor side effect of chronic anti-psychotic therapy. The pathophysiology of this disabling and commonly irreversible movement disorder continues obscure and may be caused due to GABAergic hypofunction or increased oxidative damage and free radical generation. Chronic treatment with typical antipsychotics leads to the development of abnormal hyperkinetic orofacial movements (vacuous chewing movements, tongue protrusions and facial jerking) in rats and is widely accepted as the animal model for tardive dyskinesia. Zolpidem, a GABA-mimetic drug is structurally related to melatonin and has been reported to possess anti-oxidant and neuroprotective effects both in vivo and in vitro. The study was carried out to investigate whether zolpidem can be used in the treatment of typical anti-psychotic-induced orofacial dyskinesia. Chronic haloperidol (1 mg/kg, i.p. for 21 days) and chlorpromazine (5 mg/kg, i.p. for 21 days) treatment significantly induced orofacial hyperkinetic movements and zolpidem [N, N, 6-trimethyl-2-p-tolyl-imidazo (1, 2-a) pyridine 3-acetamideL-(+)] dose dependently (1, 2, 5 mg/kg i.p. for 21 days) reduced these haloperidol and chlorpromazine-induced hyperkinetic orofacial movements. Biochemical analysis revealed that haloperidol and chlorpromazine treatment significantly induced increase in lipid peroxidation and decrease in the levels of total nitric oxide levels, non-protein thiols (NPSH) and of anti-oxidant defense enzymes, superoxide dismutase (SOD) and catalase in the striatum of rat brain. Co-administration of zolpidem (1, 2, 5 mg/kg i.p. for 21 days) significantly reduced the lipid peroxidation and restored the non-protein thiols and total nitric oxide levels induced by chronic haloperidol and chlorpromazine treatment. It also significantly reversed the haloperidol and chlorpromazine-induced decrease in brain SOD and catalase activity. Neurochemical analysis (Neurotransmitter and their metabolite level estimation) revealed that haloperidol and chlorpromazine significantly decreased the dopamine, norepinephrine and serotonin levels in brain homogenates where as it caused a significant increase in the metabolite (VMA and HVA) levels in urine, which were significantly reversed by zolpidem at higher doses. Result of the present study support the therapeutic use of zolpidem in the treatment of typical anti-psychotic-induced orofacial dyskinesia.